{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:30:52Z","timestamp":1792467052083,"version":"4.5.0"},"reference-count":91,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T00:00:00Z","timestamp":1639699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Predominantly antibody deficiencies (PAD) are a heterogeneous group of disorders characterized by dysfunctional antibody production, low immunoglobulin levels in serum and impaired vaccine responses. The clinical picture is variable, ranging from mild symptoms to severe complications, which may include autoimmunity, gastrointestinal disease, allergy, and malignancies. If left untreated, PAD patients are at risk of enduring disease progression, irreversible organ damage, and reduced life expectancy. A timely diagnosis has been shown to significantly improve disease prognosis. Here, we report on our experience using targeted gene panel sequencing by employing Agilent\u2019s HaloPlex or SureSelect and Illumina\u2019s MiSeq technologies in a cohort of 291 individuals who presented with low or absent immunoglobulin levels in combination with or without other clinical features. In total, we have detected over 57 novel or previously reported relevant mutations in\n                    <jats:italic>ADA, ADA2, BTK, CTLA4, LRBA, NFKB1, NFKB2, PIK3CD, STAT3<\/jats:italic>\n                    , and\n                    <jats:italic>TNFRSF13B<\/jats:italic>\n                    . Overall, a genetic diagnosis could be made in 24.7% of the investigated patients. The percentage of coverage for the targeted regions ranged from 90% to 98% in this study. Moreover, functional assays were performed on a defined group of the patients carrying candidate variants in\n                    <jats:italic>CTLA4<\/jats:italic>\n                    ,\n                    <jats:italic>LRBA<\/jats:italic>\n                    ,\n                    <jats:italic>NFKB1<\/jats:italic>\n                    and\n                    <jats:italic>BTK<\/jats:italic>\n                    , which confirmed their deleterious effect on protein expression and\/or function. This study reiterates that the immunological heterogeneity of predominantly antibody deficiencies may have a diverse genetic origin, although certain clinical features may hint towards a specific group of defects. Employing targeted sequencing panels proves to be a very time- and cost-efficient, yet reliable, method for the establishment of a genetic diagnosis in individuals with PAD. However, in case of negative panel results, or if functional testing reveals inconspicuous observations in patients with a clear indication for genetic testing, further work-up including whole exome or whole genome sequencing should be considered.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2021.786516","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T23:56:57Z","timestamp":1639699017000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":47,"title":["Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study"],"prefix":"10.3389","volume":"12","author":[{"given":"Jessica","family":"Rojas-Restrepo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Caballero-Oteyza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Huebscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Haberstroh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Fliegauf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baerbel","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Kobbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Warnatz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Ehl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Proietti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodo","family":"Grimbacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3466","article-title":"Primary Antibody Deficiencies","volume":"13","author":"Durandy","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1097\/ACI.0b013e32835914b9","article-title":"The Many Faces of the Clinical Picture of Common Variable Immune Deficiency","volume":"12","author":"Resnick","year":"2012","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2019.07.014","article-title":"Autoimmunity in Common Variable Immunodeficiency","volume":"123","author":"Agarwal","year":"2019","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/361226a0","article-title":"The Gene Involved in X-Linked Agammaglobulinaemia is a Member of the Src Family of Protein-Tyrosine Kinases","volume":"361","author":"Vetrie","year":"1993","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1007\/s10875-015-0201-1","article-title":"Primary Immunodeficiency Diseases: An Update on the Classification From the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015","volume":"35","author":"Picard","year":"2015","journal-title":"J Clin Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1007\/s10875-019-00737-x","article-title":"Human Inborn Errors of Immunity: 2019 Update on the Classification From the International Union of Immunological Societies Expert Committee","volume":"40","author":"Tangye","year":"2020","journal-title":"J Clin Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-00980-1","article-title":"The Ever-Increasing Array of Novel Inborn Errors of Immunity: An Interim Update by the IUIS Committee","volume":"41","author":"Tangye","year":"2021","journal-title":"J Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0012-x","article-title":"Clinical Implications of Systematic Phenotyping and Exome Sequencing in Patients With Primary Antibody Deficiency","volume":"21","author":"Abolhassani","year":"2019","journal-title":"Genet Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-02-141937","article-title":"Relevance of Biallelic Versus Monoallelic TNFRSF13B Mutations in Distinguishing Disease-Causing From Risk-Increasing TNFRSF13B Variants in Antibody Deficiency Syndromes","volume":"113","author":"Salzer","year":"2009","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2000.01131.x","article-title":"Selective IgA Deficiency (SIgAD) and Common Variable Immunodeficiency (CVID)","volume":"120","author":"Hammarstr\u00f6m","year":"2000","journal-title":"Clin Exp Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000929","article-title":"Current Genetic Landscape in Common Variable Immune Deficiency","volume":"135","author":"Abolhassani","year":"2000","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation.V2012.1.301.3798316","article-title":"The Many Faces of Common Variable Immunodeficiency","volume":"2012","author":"Cunningham-Rundles","year":"2012","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.04.049","article-title":"Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency","volume":"136","author":"Bonilla","year":"2014","journal-title":"J\u00a0Allergy Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2009.07669.x","article-title":"Update in Understanding Common Variable Immunodeficiency Disorders (CVIDs) and the Management of Patients With These Conditions","volume":"145","author":"Chapel","year":"2009","journal-title":"Br J Haematology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1007\/s11882-014-0468-y","article-title":"Utility of Next Generation Sequencing in Clinical Primary Immunodeficiencies","volume":"14","author":"Raje","year":"2014","journal-title":"Curr Allergy Asthma Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map Format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.37","article-title":"Sherloc: A Comprehensive Refinement of the ACMG-AMP Variant Classification Criteria","volume":"19","author":"Nykamp","year":"2017","journal-title":"Genet Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3746","article-title":"Autosomal Dominant Immune Dysregulation Syndrome in Humans With CTLA4 Mutations","volume":"20","author":"Schubert","year":"2014","journal-title":"Nat Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00720","article-title":"Rapid Flow Cytometry-Based Test for the Diagnosis of Lipopolysaccharide Responsive Beige-Like Anchor (LRBA) Deficiency","volume":"9","author":"G\u00e1mez-D\u00edaz","year":"2018","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"eaat4941","DOI":"10.1126\/sciimmunol.aat4941","article-title":"ZNF341 Controls STAT3 Expression and Thereby Immunocompetence","volume":"3","author":"Frey-Jakobs","year":"2018","journal-title":"Sci Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646632","article-title":"Guidelines for the Use of Flow Cytometry and Cell Sorting in Immunological Studies","volume":"49","author":"Cossarizza","year":"2017","journal-title":"Eur J Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700079","article-title":"High SYK Expression Drives Constitutive Activation of CD21 Low B Cells","volume":"198","author":"Keller","year":"2017","journal-title":"J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.621503","article-title":"A Pathogenic Missense Variant in NFKB1 Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage","volume":"12","author":"Fliegauf","year":"2021","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.02.055","article-title":"Phenotype, Penetrance, and Treatment of 133 Cytotoxic T-Lymphocyte Antigen 4\u2013Insufficient Subjects","volume":"142","author":"Schwab","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02012","article-title":"Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers","volume":"9","author":"Egg","year":"2018","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.11.051","article-title":"Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous NFKB1 Mutations","volume":"146","author":"Lorenzini","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"8390356","DOI":"10.1155\/2016\/8390356","article-title":"Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes","volume":"2016","author":"Pulvirenti","year":"2016","journal-title":"J Immunol Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.05.012","article-title":"TNF Receptor Superfamily Member 13b (TNFRSF13B) Hemizygosity Reveals Transmembrane Activator and CAML Interactor Haploinsufficiency at Later Stages of B-Cell Development","volume":"136","author":"Romberg","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2007.10.001","article-title":"Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor Mutations in Common Variable Immunodeficiency: Clinical and Immunologic Outcomes in Heterozygotes","volume":"120","author":"Zhang","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.jaci.2011.01.048","article-title":"Functional Analysis of Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor (TACI) Mutations Associated With Common Variable Immunodeficiency","volume":"128","author":"Fried","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-11-189720","article-title":"The Murine Equivalent of the A181E TACI Mutation Associated With Common Variable Immunodeficiency Severely Impairs B-Cell Function","volume":"114","author":"Lee","year":"2009","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2012.10.029","article-title":"TACI Mutations and Impaired B-Cell Function in Subjects With CVID and Healthy Heterozygotes","volume":"131","author":"Martinez-Gallo","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-009-9317-5","article-title":"Novel Mutations in TACI (TNFRSF13B) Causing Common Variable Immunodeficiency","volume":"29","author":"Mohammadi","year":"2009","journal-title":"J Clin Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-01-829424","article-title":"Oncogenic Activation of the STAT3 Pathway Drives PD-L1 Expression in Natural Killer\/T-Cell Lymphoma","volume":"132","author":"Song","year":"2018","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","first-page":"104144","DOI":"10.1016\/j.ejmg.2021.104144","article-title":"Recurrent Necrotizing Cellulitis, Multi-Organ Autoimmune Disease and Humoral Immunodeficiency Due to a Novel NFKB1 Frameshift Mutation","volume":"64","author":"Bergbreiter","year":"2021","journal-title":"Eur J Med Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00297","article-title":"Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2","volume":"10","author":"Klemann","year":"2019","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/art.40147","article-title":"Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood","volume":"69","author":"Schepp","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1307361","article-title":"Early-Onset Stroke and Vasculopathy Associated With Mutations in ADA2","volume":"370","author":"Zhou","year":"2014","journal-title":"N Engl J Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210802","article-title":"ADA2 Deficiency (DADA2) as an Unrecognised Cause of Early Onset Polyarteritis Nodosa and Stroke: A Multicentre National Study","volume":"76","author":"Caorsi","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00303","article-title":"Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome","volume":"7","author":"Aird","year":"2019","journal-title":"Front Pediatr"},{"key":"B41","doi-asserted-by":"publisher","first-page":"108316","DOI":"10.1016\/j.clim.2019.108316","article-title":"Distinct Molecular Response Patterns of Activating STAT3 Mutations Associate With Penetrance of Lymphoproliferation and Autoimmunity","volume":"210","author":"J\u00e4gle","year":"2020","journal-title":"Clin Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.ajhg.2015.07.008","article-title":"Haploinsufficiency of the NF-\u03baB1 Subunit P50 in Common Variable Immunodeficiency","volume":"97","author":"Fliegauf M","year":"2015","journal-title":"Am J Hum Genet"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.09.025","article-title":"The Extended Phenotype of LPS-Responsive Beige-Like Anchor Protein (LRBA) Deficiency","volume":"137","author":"G\u00e1mez-D\u00edaz","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-09-602763","article-title":"Early-Onset Lymphoproliferation and Autoimmunity Caused by Germline STAT3 Gain-of-Function Mutations","volume":"125","author":"Milner","year":"2015","journal-title":"Blood"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3040","article-title":"Activating Germline Mutations in STAT3 Cause Early-Onset Multi-Organ Autoimmune Disease","volume":"46","author":"Flanagan","year":"2014","journal-title":"Nat Genet"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1380010214","article-title":"Identification of Two New Missense Mutations (R156C and S291L) in Two ADA\u2013 SCID Patients Unusual for Response to Therapy With Partial Exchange Transfusions","volume":"1","author":"Hirschhorn","year":"1992","journal-title":"Hum Mutat"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02618","article-title":"Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1","volume":"10","author":"Schr\u00f6der","year":"2019","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-009-9341-5","article-title":"Clinical Characteristics and Genotype-Phenotype Correlation in 62 Patients With X-Linked Agammaglobulinemia","volume":"30","author":"Lee","year":"2010","journal-title":"J Clin Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1086\/301828","article-title":"Mutations in Btk in Patients With Presumed X-Linked Agammaglobulinemia","volume":"62","author":"Conley","year":"1998","journal-title":"Am J Hum Genet"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1111\/j.1744-313X.2006.00598.x","article-title":"Identification of Bruton Tyrosine Kinase Mutations in 12 Chinese Patients With X-Linked Agammaglobulinaemia by Long PCR-Direct Sequencing","volume":"33","author":"Chan","year":"2006","journal-title":"Int J Immunogenet"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13163","article-title":"Clinical Efficacy of a Next-Generation Sequencing Gene Panel for Primary Immunodeficiency Diagnostics","volume":"93","author":"Rae","year":"2018","journal-title":"Clin Genet"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2018.07.012","article-title":"High Frequencies of Asymptomatic Epstein-Barr Virus Viremia in Affected and Unaffected Individuals With CTLA4 Mutations","volume":"195","author":"Hoshino","year":"2018","journal-title":"Clin Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1111\/j.1744-313X.2006.00627.x","article-title":"Identification of Variations in the Human Phosphoinositide 3-Kinase P110? Gene in Children With Primary B-Cell Immunodeficiency of Unknown Aetiology","volume":"33","author":"Jou","year":"2006","journal-title":"Int J Immunogenet"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1126\/science.1243292","article-title":"Phosphoinositide 3-Kinase Gene Mutation Predisposes to Respiratory Infection and Airway Damage","volume":"342","author":"Angulo","year":"2013","journal-title":"Science"},{"key":"B55","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/ni.2771","article-title":"Dominant-Activating Germline Mutations in the Gene Encoding the PI(3)K Catalytic Subunit P110\u03b4 Result in T Cell Senescence and Human Immunodeficiency","volume":"15","author":"Lucas","year":"2014","journal-title":"Nat Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000929","article-title":"Current Genetic Landscape in Common Variable Immune Deficiency","volume":"135","author":"Abolhassani","year":"2020","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00220","article-title":"Genetic Diagnosis Using Whole Exomesequencing in Common Variable Immunodeficiency","volume":"7","author":"Maffucci","year":"2016","journal-title":"Front Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/ng1600","article-title":"Mutations in TNFRSF13B Encoding TACI are Associated With Common Variable Immunodeficiency in Humans","volume":"37","author":"Salzer","year":"2005","journal-title":"Nat Genet"},{"key":"B59","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/gene.2011.55","article-title":"Rare Mutations in TNFRSF13B Increase the Risk of Asthma Symptoms in Swedish Children","volume":"13","author":"Janzi","year":"2012","journal-title":"Genes Immun"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/ng0407-429","article-title":"Reexamining the Role of TACI Coding Variants in Common Variable Immunodeficiency and Selective IgA Deficiency","volume":"39","author":"Pan-Hammarstr\u00f6m","year":"2007","journal-title":"Nat Genet"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.145136","article-title":"Specific Antibody Deficiency and Autoinflammatory Disease Extend the Clinical and Immunological Spectrum of Heterozygous NFKB1 Loss-of-Function Mutations in Humans","volume":"101","author":"Schipp","year":"2016","journal-title":"Haematologica"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.10.054","article-title":"Damaging Heterozygous Mutations in NFKB1 Lead to Diverse Immunologic Phenotypes","volume":"140","author":"Kaustio","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B63","doi-asserted-by":"publisher","first-page":"e20210566","DOI":"10.1084\/jem.20210566","article-title":"Biochemically Deleterious Human NFKB1 Variants Underlie an Autosomal Dominant Form Of Common Variable Immunodeficiency","volume":"218","author":"Li","year":"2021","journal-title":"J Exp Med"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.06.050","article-title":"Nuclear Factor \u03baB Mutations in Human Subjects: The Devil is in the Details","volume":"142","author":"Fliegauf","year":"2018","journal-title":"J Allergy Clin Immunol United States"},{"key":"B65","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.clim.2016.11.012","article-title":"NFKB1 Regulates Human NK Cell Maturation and Effector Functions","volume":"175","author":"Lougaris","year":"2017","journal-title":"Clin Immunol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.09.009","article-title":"Germline Mutations in NFKB2 Implicate the Noncanonical NF-\u03baB Pathway in the Pathogenesis of Common Variable Immunodeficiency","volume":"93","author":"Chen","year":"2013","journal-title":"Am J Hum Genet"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-782177","article-title":"Novel Nonsense Gain-of-Function NFKB2 Mutations Associated With a Combined Immunodeficiency Phenotype","volume":"130","author":"Kuehn","year":"2017","journal-title":"Blood"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.04.039","article-title":"Therapeutic Options for CTLA-4 Insufficiency","author":"Egg","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.jaci.2012.05.043","article-title":"LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation in a Family With Inflammatory Bowel Disease and Combined Immunodeficiency","volume":"130","author":"Alangari","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1663","article-title":"Patients With LRBA Deficiency Show CTLA4 Loss and Immune Dysregulation Responsive to Abatacept Therapy","volume":"349","author":"Lo","year":"2015","journal-title":"Science"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207567","article-title":"Deregulated Expression of LRBA Facilitates Cancer Cell Growth","volume":"23","author":"Wang","year":"2004","journal-title":"Oncogene"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(97)80107-0","article-title":"Role of Btk in B Cell Development and Signaling","volume":"9","author":"Desiderio","year":"1997","journal-title":"Curr Opin Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00636","article-title":"Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond","volume":"9","author":"de Valles-Ib\u00e1\u00f1ez","year":"2018","journal-title":"Front Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.05.046","article-title":"Improving the Diagnostic Efficiency of Primary Immunodeficiencies With Targeted Next-Generation Sequencing","volume":"147","author":"Fusaro","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00531","article-title":"Targeted NGS: A Cost-Effective Approach to Molecular Diagnosis of PIDs","volume":"5","author":"Stoddard","year":"2014","journal-title":"Front Immunol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02325","article-title":"Expanding the Clinical and Genetic Spectra of Primary Immunodeficiency-Related Disorders With Clinical Exome Sequencing: Expected and Unexpected Findings","volume":"10","author":"Rudilla","year":"2019","journal-title":"Front Immunol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.06.049","article-title":"Clinical, Immunologic, and Genetic Spectrum of 696 Patients With Combined Immunodeficiency","volume":"141","author":"Abolhassani","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.191","article-title":"Whole-Exome Sequencing in Undiagnosed Genetic Diseases: Interpreting 119 Trios","volume":"17","author":"Zhu","year":"2015","journal-title":"Genet Med"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.00485","article-title":"Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders","volume":"10","author":"Gao","year":"2019","journal-title":"Front Genet"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12654","article-title":"Utility of Whole-Exome Sequencing for Those Near the End of the Diagnostic Odyssey: Time to Address Gaps in Care","volume":"89","author":"Sawyer","year":"2016","journal-title":"Clin Genet"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2015-103690","article-title":"Genes Associated With Common Variable Immunodeficiency: One Diagnosis to Rule Them All","volume":"53","author":"Bogaert","year":"2016","journal-title":"J Med Genet"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-213025","article-title":"Role of TNFRSF13B Variants in Patients With Common Variable Immunodeficiency","volume":"114","author":"Martinez-Pomar","year":"2009","journal-title":"Blood"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1038\/ng0407-430","article-title":"Reexamining the Role of TACI Coding Variants in Common Variable Immunodeficiency and Selective IgA Deficiency","volume":"39","author":"Castigli","year":"2007","journal-title":"Nat Genet"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2015.05.020","article-title":"Application of Whole Genome and RNA Sequencing to Investigate the Genomic Landscape of Common Variable Immunodeficiency Disorders","volume":"160","author":"van Schouwenburg","year":"2015","journal-title":"Clin Immunol"},{"key":"B85","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1016\/j.jaci.2015.08.049","article-title":"Common Variable Immunodeficiency and Natural Killer Cell Lymphopenia Caused by Ets-Binding Site Mutation in the IL-2 Receptor \u03b3 (IL2RG) Gene Promoter","volume":"137","author":"Chandra","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.01.041","article-title":"Presence of Hypogammaglobulinemia and Abnormal Antibody Responses in GATA2 Deficiency","volume":"134","author":"Chou","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.04.042","article-title":"A Hypomorphic Recombination-Activating Gene 1 (RAG1) Mutation Resulting in a Phenotype Resembling Common Variable Immunodeficiency","volume":"134","author":"Abolhassani","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B88","doi-asserted-by":"publisher","first-page":"e12811","DOI":"10.1111\/sji.12811","article-title":"Impaired Polysaccharide Responsiveness Without Agammaglobulinaemia in Three Patients With Hypomorphic Mutations in Bruton Tyrosine Kinase\u2014No Detection by Newborn Screening for Primary Immunodeficiencies","volume":"91","author":"Kr\u00fcger","year":"2020","journal-title":"Scand J Immunol"},{"key":"B89","doi-asserted-by":"publisher","first-page":"e0133220","DOI":"10.1371\/journal.pone.0133220","article-title":"Leaky RAG Deficiency in Adult Patients With Impaired Antibody Production Against Bacterial Polysaccharide Antigens","volume":"10","author":"Geier","year":"2015","journal-title":"PloS One"},{"key":"B90","article-title":"Common Variable Immunodeficiency or Late-Onset Combined Immunodeficiency: A New Hypomorphic JAK3 Patient and Review of the Literature","volume":"25","author":"Abolhassani","year":"2015","journal-title":"J Investig Allergol Clin Immunol"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.10.1899","article-title":"Unique Mutations of Bruton\u2019s Tyrosine Kinase in Fourteen Unrelated X-Linked Agammaglobulinemia Families","volume":"3","author":"Zhu","year":"1994","journal-title":"Hum Mol Genet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.786516\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T23:57:02Z","timestamp":1639699022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.786516\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,17]]},"references-count":91,"alternative-id":["10.3389\/fimmu.2021.786516"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.786516","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,17]]},"article-number":"786516"}}